Early life trauma is thought to influence numerous biological systems that affect the ability of an individual to properly manage stress later in life. Early life trauma can result in reduced cognitive abilities, increased impulsivity and increased risk for psychiatric disorders including post-traumatic stress disorder (PTSD), alcohol and drug use disorders and mood disorder, all of which could contribute to aberrant stress response and increased risk for fatal and nonfatal suicidal behaviors5. A growing body of evidence implicates epigenetic alterations in molecular pathways important for hypothalamic pituitary adrenal (HPA) axis function and sensitivity. For example, DNA methylation changes in the NR3C1 gene that encodes the glucocorticoid receptor (GR) are altered by maternal behavior in rats12 and are elevated in the hippocampus of suicide completers that experienced early life trauma13. The cumulative effect of these epigenetically mediated events is a reduction in GR levels that may lead to an improper ability to manage stress in later life. While a majority of research has focused on NR3C1, identification of molecular variation at other genes within this pathway may represent important mediators of stress and suicidal behavior.
Suicide represents a major public health problem with the rates of death by suicide surpassing that of motor vehicle accidents in 20091. More people die by suicide every year than homicides and all wars combined worldwide2. Suicide and suicide attempt are complex and heterogeneous phenotypes that have been a fairly intractable public health problem as annual suicide rates have been stable over the past 60 years at around 10 to 12 per 100,0003, irrespective of advances in the diagnosis and treatment of major mental disorders. Psychiatric illness is present in 90% of suicides and suicide attempters4 yet psychiatric illness is not sufficient to cause suicide phenotypes. Numerous factors have been demonstrated to influence suicide rates including but not limited to major depression, drug and alcohol abuse, stress, and traumatic events experienced during childhood such as assault and sexual abuse2,5-11. A growing consensus in the field is that suicidal behavior appears to resemble a stress response.
In light of converging evidence implicating alteration of the stress pathway with suicidal behavior, an attractive candidate for preemptively predicting suicide risk are stress hormone levels, which act as agonists for the GR. Glucocorticoids represent one of the most consistent factors associated with suicide based on both epidemiological14-16 and molecular17-19 evidence. Additionally, measuring an individual's cortisol response to stress has been identified as a promising endophenotype associated with suicide20; however, glucocorticoid levels vary drastically over the course of the day and as such cannot be easily used as a biomarker of suicide risk. Additionally, there are a number of conflicting reports on either elevated or reduced glucocorticoid responsiveness in response to early life stressors.21 Importantly, the response of an individual to environmental factors such as stress may vary based on underlying biological susceptibility, mediated potentially by genetic factors. This gene X environment interaction hypothesis has been called the diathesis-stress or dual risk hypothesis, whereby an underlying biological state mediates a highly negative reaction to stress.22-26 In light of this model, identification of the underlying genetic or epigenetic factors mediating risk to stressors would be required in order to develop an effective biomarker for stress and trauma associated morbidities such as suicidal behavior.